ROLE OF INTRAMITOCHONDRIAL ARACHIDONIC ACID IN BREAST CANCER CELLS

DUARTE ALEJANDRA; ORLANDO ULISES; CASTILLO ANA FERNANDA; DELLETIERES DREANINA; SOLANO ANGELA R; PASQUALINI MARIA EUGENIA; MALOBERTI PAULA; PODESTÁ ERNESTO J

Villa Carlos Paz, Córdoba, Argentina

Congreso; XLIV Reunión Anual de la Sociedad Argentina de Investigación en Bioquímica y Biología Molecular; 2008

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular (SAIB).

The inducible isoform of cycloxygenase COX-2 and the 5-, 12- and 15-lipoxygenases (LOX) are highly expressed in aggressive metastatic breast cancer. The acyl-CoA sinthetase (ACS4), a key enzyme in the regulation of intramitochondrial arachidonic acid (AA) release, has been implicated in colon carcinoma and hepatocellular cancer. The mechanism proposed for the role of ACS4 is the reduction of free AA levels and apoptosis. Since ACS4 is working in AA release and its metabolism to the LOX pathway, an important question is whether this mechanism is also operating in breast cancer cells. We measured the levels of 5-, 12-,15-HETE by HPLC in different human breast cancer cells line: MCF-7 (non aggressive phenotype) and in the MDA-MB-231 (aggressive phenotype). In MDA-MB-231 the levels of 5-,12-,15-HETE were 70, 5 and 2-fold higher than MCF7 cells. Inhibition of ACS4 expression in the aggressive cell line by siRNA reduced the LOX products to the levels observed in the non aggressive cell line. Overexpression of ACS4 in the non aggressive cell line produced an increase in COX2 expression that was blocked by the inhibition of LOX. The overexpression of ACS4 and COX2 correlates with the high aggressive phenotype. These results indicate that ACS4 is a key enzyme in the regulation of the synthesis of LOX products and COX-2 induction, a key enzyme in cancer progression.